title: The safety and pharmacokinetics of recombinant soluble CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. A phase 1 study.
abstract: OBJECTIVE
  To evaluate the safety and pharmacokinetics of recombinant, soluble human CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. The protein rCD4 binds to envelope protein, gp120, of the human immunodeficiency virus (HIV) and blocks HIV infection of CD4 lymphocytes in vitro.
  
  
  METHODS
  Phase 1 trial with dose escalation.
  
  
  METHODS
  Two university-affiliated hospital clinics.
  
  
  METHODS
  Of 42 subjects enrolled, 29 had AIDS and 13 had AIDS-related complex.
  
  
  METHODS
  The rCD4 was administered by rapid intravenous infusion on day 1, followed by a 3-day washout, then once a day for 10 days, followed by a 7-day washout, and then three times a week for 8 weeks. Doses of 1, 10, 30, 100, and 300 micrograms/kg body weight per day of rCD4 were administered intravenously to 6 subjects at each dose level. Twelve additional patients received 300 micrograms/kg.d of rCD4: 6 by intramuscular and 6 by subcutaneous injection. All subjects were monitored for toxicity. Immunologic and virologic variables were also monitored.
  
  
  RESULTS
  Administration of rCD4 was not associated with important toxicity as determined by clinical monitoring or by serum chemistry, hematologic, or immunologic variables. No subjects required dose reduction or discontinuation of therapy due to rCD4-related toxicity. No consistent or sustained changes in CD4 lymphocyte populations or HIV antigen levels were observed. The volume of distribution of rCD4 was small, and clearance remained constant over the dose range studied. The bioavailability of intramuscular injection and subcutaneous injection was 51% and 45%, respectively.
  
  
  CONCLUSIONS
  At the dose levels used in this study, rCD4 appears safe and well tolerated. Serum concentrations of rCD4 were achieved that were comparable to concentrations shown to have antiviral activity in vitro. Further studies are indicated to determine whether rCD4 or related molecules will be useful in treating HIV infection.
authors.affiliation: San Francisco General Hospital, California.
authors.forename: J O
authors.initials: JO
authors.lastname: Kahn
authors.forename: J D
authors.initials: JD
authors.lastname: Allan
authors.forename: T L
authors.initials: TL
authors.lastname: Hodges
authors.forename: L D
authors.initials: LD
authors.lastname: Kaplan
authors.forename: C J
authors.initials: CJ
authors.lastname: Arri
authors.forename: H F
authors.initials: HF
authors.lastname: Fitch
authors.forename: A E
authors.initials: AE
authors.lastname: Izu
authors.forename: J
authors.initials: J
authors.lastname: Mordenti
authors.forename: J E
authors.initials: JE
authors.lastname: Sherwin
authors.forename: J E
authors.initials: JE
authors.lastname: Groopman
mesh_terms: D000386:AIDS-Related Complex / Q000097:blood / Q000628:therapy*; D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000628:therapy*; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000032:analysis; D001682:Biological Availability; D015704:CD4 Antigens / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D015488:HIV Antigens / Q000097:blood; D006207:Half-Life; D006403:Hematologic Tests; D006801:Humans; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012995:Solubility
chemical_list: D000906:Antibodies; D015704:CD4 Antigens; D015488:HIV Antigens; D011994:Recombinant Proteins